Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pharmacogenet Genomics. Author manuscript; available in PMC 2010 July 1.
Published in final edited form as:
PMCID: PMC2756763

Antiestrogen pathway (aromatase inhibitor)


Estrogen plays an important role in initiating and promoting breast cancer (reviewed in [1]). Antiestrogen pathway shows the rate-limiting biosynthesis of estrogen from androgens by aromatase and its inhibition by aromatase inhibitors/inactivators in postmenopausal women (Fig. 1). Aromatase, an enzyme of the cytochrome P450 subfamily and the product of the CYP19A1 gene, is highly expressed in the placenta and in the granulose cells of ovarian follicles in premenopausal women [2]. Its expression depends on cyclical gonadotropin stimulation [3]. In addition, aromatase is also present at lower levels in several nonglandular tissues that include subcutaneous fat, liver, muscle, brain, normal breast and breast cancer tissue [4]. Estrogen production after menopause is solely from nonglandular sources, particularly subcutaneous fat. In menopause, androstenedione produced in the adrenals and, to a small extent, testosterone produced in the ovaries are released to the circulation and then sequestered to nonglandular tissues (e.g. liver and breast cells), where they are converted to estrone and estradiol, respectively, by aromatase located in these tissues [5]. In the liver and in breast tissue, estrone and estradiol undergo oxidation by cytochrome P450s to a number of hydroxylated metabolites [6]. Estrone and estradiol in these tissues also undergo conjugation by sulfotransferases or deconjugation by steroid sulfatase [7]. In all tissues, hydroxysteroid (17-beta) dehydrogenase (HSD17B) converts androstenedione to testosterone and estrone to estradiol [5].

Fig. 1
Aromatase: synthesis of estrogen in postmenopausal women and its inhibition by aromatase inhibitors.

Drugs that effectively inhibit the aromatase-mediated synthesis of estrogens in peripheral tissues including the breast, thus depriving the system of estrogens, are widely used in the treatment of breast cancer [4]. These drugs include the nonsteroidal triazole derivatives anastrozole and letrozole and the steroidal exemestane.


Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (


1. Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 2006;102:89–96. [PMC free article] [PubMed]
2. Labrie F, Simard J, Luu-The V, Pelletier G, Belghmi K, Belanger A. Structure, regulation and role of 3 beta-hydroxysteroid dehydrogenase, 17 beta-hydroxysteroid dehydrogenase and aromatase enzymes in the formation of sex steroids in classical and peripheral intracrine tissues. Baillieres Clin Endocrinol Metab. 1994;8:451–474. [PubMed]
3. Palermo R. Differential actions of FSH and LH during folliculogenesis. Reprod Biomed Online. 2007;15:326–337. [PubMed]
4. Rieber AG, Theriault RL. Aromatase inhibitors in postmenopausal breast cancer patients. J Natl Compr Canc Netw. 2005;3:309–314. [PubMed]
5. Labrie F, Luu-The V, Labrie C, Belanger A, Simard J, Lin SX, Pelletier G. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone. Endocr Rev. 2003;24:152–182. [PubMed]
6. Jefcoate CR, Liehr JG, Santen RJ, Sutter TR, Yager JD, Yue W, et al. Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr. 2000;27:95–112. Review. [PubMed]
7. Raftogianis R, Creveling C, Weinshilboum R, Weisz J. Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr. 2000;27:113–124. Review. [PubMed]